FDA-Approved Medications: New Data

This newly approved disease-modifying therapy is an anti-CD20 monoclonal antibody. Although similar to the experimental medication Rituxan, Ocrevus has the potential advantage of being a more humanized antibody than Rituxan. As noted in the introduction to the section on monoclonal antibodies (under “Experimental Medications”), humanized monoclonal antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans.

In a Phase II study of ocrelizumab1 in 220 individuals with RRMS, reductions in the total number of brain lesions detected by MRI scans (the primary endpoint of the study) were highly significant at 96 percent for 2,000 mg ocrelizumab and 89 percent for 600 mg compared to placebo. The annualized relapse rate was significantly lower versus placebo at week 24, with a reduction of 73 percent for ocrelizumab 2,000 mg, and 80 percent for ocrelizumab 600 mg. Ocrelizumab’s effectiveness was maintained through week 72; the proportion of relapse-free patients at week 72 was 84 percent for the 600 mg group, and 82 percent for the 2,000 mg group.

The findings of three important studies of ocrelizumab in MS were announced in 2015.2 In relapsing MS, ocrelizumab met both the primary and major secondary endpoints in the Phase III, OPERA I and OPERA II studies. The OPERA studies had identical designs. The total combined enrollment for both studies was 1,656, which included individuals with relapsing forms of MS who either had relapsing-remitting MS or secondary-progressive MS with relapses.

Taking place at 307 sites in 40 countries, individuals received either 600 mg of ocrelizumab via intravenous (IV) infusion every six months, or the approved 44 mcg dose of Rebif® (interferon beta-1a), given via subcutaneous injection three-times weekly. Participants given ocrelizumab had significant reductions in both studies in annualized relapse rate of 46 and 47 percent over a two-year period versus the interferon groups. Additionally, in the ocrelizumab groups, new MRI lesions were decreased by 94 and 95 percent, brain atrophy was decreased by 24 and 25 percent, and progression of sustained clinical disability was decreased by 40 percent.

The third ocrelizumab study, ORATORIO, was conducted in patients with PPMS. Prior to this study, no Phase III studies in PPMS had been successful, despite multiple attempts. ORATORIO was a randomized, double-blind, and global multi-center trial that studied the effectiveness and safety of ocrelizumab compared to placebo in 732 people with PPMS. Every six months, two 300 mg infusions (for a total of 600 mgs) were given two weeks apart. Members of the treatment group were compared to a placebo group. The primary endpoint of this study was time to the onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

The ORATORIO study met its primary endpoint, showing that treatment with ocrelizumab significantly reduced the progression of clinical disability (sustained for at least 12 weeks) by 24 percent compared with placebo. Walking speed, as measured by the timed 25-foot walk, was improved by 29 percent. MRI hyper-intense T2 lesions were actually reduced by ocrelizumab, and brain-volume loss as viewed on MRI was reduced by 17.5 percent. In conclusion, this is the first study where a disease-modifying therapy has shown effectiveness in treating PPMS. The incidence of adverse events associated with ocrelizumab was similar to placebo; the most common adverse events were mild-to-moderate infusion-related reactions.3

Although Phase III trials in rheumatoid arthritis reported significant rates of serious and opportunistic infections, and one patient died of a systemic inflammatory response of unknown cause, the number of serious adverse events in the ORATORIO, OPERA I, and OPERA II studies were small and similar among the groups, and no opportunistic infections were identified in these trials. (Opportunistic infections are a result of micro-organisms found in the body that only infect a person with a weakened immune system.)

As might be expected, more infusion-related reactions were seen in the ocrelizumab groups versus placebo. Importantly, several more cases of cancer were seen in the ocrelizumab groups versus the control patients. The possible association of ocrelizumab to the development of cancer will be carefully reviewed to assess if this represents a safety concern with this agent, as this also may be a chance finding.

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Last Update: Monday, May 22, 2017

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